IRACON 2016

Management of Lupus Nephritis: Old is gold, New is Trendy

First episode of LN (III/IV): Induction

ACR guidelines, 2012

Low dose is equally considerable as high dose CYC

Switch to the other agent if no improvement at 6 monthsAgain, low dose is equally considerable as high dose

Crescentic LN in ELNT

• ELNT patients: Few had severe renal diseaseRPRF>50% segmental necrosis / crescents

• ACR recommendations:CYC or MMF in same doses as non-crescentic GNi.v. Methylprednisolone pulse – 3 dosesOral steroids at 1 mg/kg dose

Arthritis & Rheumatism, 2002

First episode (Class V): Induction

Proteinuria remission rate at 6 months: 70%

EULAR recommendations

• High dose CYC preferable to low dose CYC if:Acute deterioration in renal functionCellular crescents on renal histologyFibrinoid necrosis on renal histology

• 3 more pulses of i.v. MP if no improvement by 3 months

• AZA as an induction agent when CYC/MMF are contraindicated

First episode of LN (Class II): Induction

• KDIGO recommendation: Based on proteinuria<1gm/d: Steroids + steroid sparing agent guided by extra-renal manifestations>3gm/d: Steroids + CNIs as in MCD

• EULAR Recommendation:RAAS blockadeSteroids ± AZA if proteinuria ≥1 gm/d

• ACR recommendation: Need for immunosuppressive to be guided by extra-renal manifestations

N Engl J Med 1978; 299: 1151–1155

N Engl J Med 1978; 299: 1151–1155

Austin; NEJM 1986- NIH Trial

Five Protocols for Lupus Nephritis 1969- 1986

1.High dose oral Pred for 4-8 weeks than taper2.Aza + Low dose Pred3.CyP oral +Pred4.CyP + Aza + Pred5.IV CyP + Low dose Pred

N Engl J Med 1986; 314: 614–619

N Engl J Med 1986; 314: 614–619

• 2nd NIH: 3 treatments were compared: – Monthly intravenous cyclophosphamide for 6 months, – Same followed by quarterly cyclophosphamide pulses

for an additional 2 years, – Monthly methylprednisolone pulses for 6 months.

• Pulse methylprednisolone had a higher probability of doubling serum creatinine in comparison with patients assigned to cyclophosphamide.

• Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduced the rate of exacerbations

Lancet 1992; 340: 741-745

• 3rd NIH trial:– Bolus therapy with methylprednisolone (1 g/m2

body surface area), given monthly for at least 1 year;

– Bolus therapy with cyclophosphamide (0.5-1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or

– Bolus therapy with both methylprednisolone and cyclophosphamide

• Monthly methylprednisolone was less effective than monthly cyclophosphamide. A non significant trend toward greater efficacy with combination therapy was seen

Ann. Intern Med. 1996; 125: 549-557

Standard of treatment

• Cyclophosphamide Pulses- 0.5-0.75 gm/m2 monthly pulses = 6 Quarterly pulses X 11/2 year = 6 Six monthly x 1 year = 2 Total = 14

pulses

• Methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year;

Ann. Intern Med. 1996; 125: 549-557

ELNT

90 patients of Proliferative LN

High dose CyP Low dose CyP (6 monthly + 2 quar) (6 fortnightly f/b Aza)

FU 41 m FU 41.3 m

• Renal Remiss 59 % 71% (ns)• Renal Flare 29% 27%

Low dose was comparable to high dose in Caucasians

Arthritis Rheum. 2002; 46: 2121-31

Arthritis Rheum. 2002; 46: 2121-31

ELNT - 10 year FU - ESRD

Ann Rheum Dis 2010; 69: 61-64.

ELNT

• Only 22% presented with renal impairment and 28% presented with nephrotic syndrome, compared with 64% and 62% respectively, in the study by Boumpas et al.

• Milder cases of proliferative lupus nephritis, for which less-aggressive treatment is certainly justified.

• Few black or African Caribbean patients were included in the ELNT (9% of the cohort)

Early Vs current studies

Measures

• Urine analysis– RBC’s– WBC’s– Casts – RBC/WBC

• Creatinine• Proteinuria

• Part of global outcome indices /measures

• Renal specific

Response criteria used in various trials

Guidelines compared

Where MMF has scored superiority/ non –inferior to Cyclophosphamide?

1.Induction - LN2.Maintenance therapy,3.Membranous Lupus nephritis(Class V)4.Side effect profile5.Paediatric LN – Pubertal Male

InductionALMS

Multicentre – MMF(3000mg) Vs IV CYC Pulse Designed as a Superiority trialNo difference between two groups in establishing CR

Blacks and Hispanics responded better to MMFAsians and Whites failed to show a difference

Contrerars et al.

Maintenance therapy

IV quarterly Cyclo Vs MMF/Aza

ConclusionIn proliferative lupus nephritis, short-term therapy with ivcyclo followed by maintenance therapy with MMF or AZA appears to be more efficacious and safer than long-term therapy with intravenouscyclophosphamide

MMF as Maintenance Therapy

Conclusion:We conclude that mycophenolate mofetil is superior to azathioprine in maintaining the renal response to treatment and in preventing relapse in patients with active lupus nephritis who have had a clinical response to induction therapy with either mycophenolate mofetil or intravenous cyclophosphamide.

Long Term follow up of MAINTAIN cohort fail to unmask differences between MMF and AZA as maintenance therapy of LN

Annals of Rheumatic Diseases 2015, March

Membranous nephritisUniform recommendationsACREULAR/EDTA-ERARecommends Steroids + ACEi + MMF for Class V Lupus

nephritis with nephrotic range of proteinuria±CNI s

Side Effect profile of MMF VS Cyclo

Gonadal Toxicity

Role of MMF is Still Unproven1.Severe LN2.LN with extra renal manifestations(NPLSE)3.Long term data Single agent which has shown

reduction in the incidence of ESRD and CKD

LN: Biomarkers to guide therapy

• Recommended: Renal BiopsyProteinuria / Spot UPCRActive sedimentSerum creatinine / eGFR

• Assessment:At 3 months: Look for non-worseningAt 6 months: Look for ‘at least’ partial responseComplete response: May take upto 12 months

28 year unmarried postgraduate in medicine presented with nephrotic syndromeClass V lupus nephritis.proteinuria of 2.4 gm/d, no active sediment , normal renal function. serum albumin is 2.5 gm/L.no extrarenal manifestations.

What would be the best treatment option in this patient with membranous lupus nephritis?

•0.5mg/kg steroids with ELNT cyclophosphamide•0.5 mg/kg steroids with high dose cyclophosphamide•0.5-0.75 mg/kg steroids with Mycophenolate mofetil.•0.5 mg/kg steroids with Rituximab •Only RAAS with 0.5 mg/kg steroids

A 18 year old girl diagnosed SLE since Nov 2013.

April 14: proteinuria of 2.7 gms/d, hematuria: rituximab 1 gm with 3 gm iv methylprednisolone pulses. Her proteinuria decreased to 800 mg/d. Therapy was interrupted due to pulmonary tuberculosis.

June 14: proteinuria 5 gm/d. MMF started.

Jan 15 to Aug 15 proteinuria was 730 mg/d

Sep 15: proteinuria 3gm/d due to non-compliance

Jan 16: Renal biopsy: Class IV and V LN

Jan to Jun 16: received 6.1 gm cumulative cyclophosphamide over 6 months followed by MMF 2 gm/d

2/16 3/16 4/16 5/16 9/16 11/16

Urine albumin 3+ 4+ 4+ 1+ 0 1+

urine RBC 16 12 5 5 7 12

urine puscells 10 10 10 12 nil 9

Urine casts nil nil nil nil nil nil

Spot PCR 3.1 0.87 0.46 0.37

24 hr urine protein gm/d

2.2 0.78

Drugs cyc cyc cyc cyc--MMF

MMF MMF

QUESTION TO AUDIENCE

1.Is the patient in remission.1. Yes2. No

Proliferative Lupus NephritisIII/IV

Membranous LN

MMF + Steroids Cyclo +Steroids MMF+ Steroids

RESISTANT RESISTANT

Cyclo+Steroids

Add or SwitchCNI s + SteroidsCyclo + Steroids

MMF +Steroids

Add or Switch CNI s+ Steroids RESISTANT

Switch or AddRituximab

Switch or AddRituximab

Observational studies: Rituximab

• 11 observational studies (5 retrospective, 6 prospective) 2003-2013

• 201 patients - >90% refractory• 375mg/m2 * 4 weeks or 1g * 2 • Background immunosuppression (CYC/MMF)

continued in 8 trials, follow up 6-12 months• CR of 36.1%, PR of 37.4%B Duxbury et al. Rituximab in systemic lupus erythematosus: an updated

systematic review and meta-analysis. Lupus (2013) 22, 1489–1503

Registry data: Rituximab

• French Autoimmunity and rituximab – 23/31 with LN responding

• UK BIOGEAS and other European cohorts: 126 patients of LN received RTX, either refractory or relapsed, 67% response rates

• Class V showed least response Terrier B, Amoura Z, Ravaud P, et al. Safety and efficacy of rituximab in

systemic lupus erythematosus: Results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010; 62: 2458–2466.

Diaz-Lagares C, Croca S, Sangle S, et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: Pooled data from European cohorts. Autoimmun Rev 2012; 11

Randomised controlled trial: LUNAR

CR, PR and NR at 52 weeks

CR PR Overall response

LUNAR – the flip side or the brighter side?

• Background immunosuppression• Selection of cases – induction , Class V LN• Differences in partial response• Ethnicity differences

Post 2013 – Intensified B cell depletion therapy

• RTX : 375 mg/m2 on days 2, 8, 15, and 22. Two more doses: 1 and 2 months

following the last weekly infusion.

• 10 mg/kg cyclophosphamide (days 4 and 17) and 3 iv pulses of 15 mg/kg (days 1, 4, and 8) methylprednisolone followed by oral prednisone, 0.8 mg/ kg/day for 2 weeks rapidly tapered until 5 mg in 3 months.

• Patients had been followed-up for a mean of 44.5 (24–93)months.• Proteinuria (baseline: 4.9 g/24 h; 3 months: 0.97; end of follow-up: 0.22)

Of the 12 patients, 9 (75%) have remained well after one cycle of IBCDT, with no flare (mean 51.6 months [25–93]).

• Three patients relapsed after 36, 41, and 72 months, respectively. Following re-treatment, they again showed complete remission over 18–48 months of observationAutoimmunity Reviews 14 (2015) 1123–1130

Long term renal survival: Predictors

Lupus, 2016

Lupus, 2016

Predictors of renal survival: Flares

Lupus, 2003

Renal survival prediction by biomarkers

Lupus, 2016Cohort 1 n=28 (Pediatric); Cohort 2 n=69 (Adult)

Renal survival prediction by biomarkers

Lupus, 2016

Total follow-up period: 60 months, Mean follow-up period at decline: 6 monthsTotal renal function decline: 29% and 30%

LN flares: what does the literature say?

42 patients with DPGN

21 for MMF 21 for Oral CYC

Maintenance: Low dose steroids with azathioprine for next 6 months

Relapse rate: 15% Relapse rate: 11%

NEJM, 2000

Induction with steroids + DMARD

6 months 6 months

6 months 6 months

Predictors and risk of LN flare

55 LN: DPGN

CR: 37 PR: 12

6-9 months oral CYC AZA

After 1 year

Follow-up: relapse of LN/doubling of Cr

Median follow-up: 48 monthsRisk of renal flare:6% at 1 year21% at 3 years32% at 5 yearsMedian time to flare: 43 monthsPredictors:ing creatinineHigh histologic activity scoreLower cumulative dose of CYC

Euro-Lupus Nephritis Trial

LD HD

Median Follow-up (months) 41.3 41

Treatment failure (%) 16 20

Renal remission (%) 71 54

Renal flare rate (%) 27 29

LN flares: Conventional serum markers46 LN patients, Follow-up: 64 months, Relapse: 17 at mean 40 months

Lupus, 2003

2012KDIGOMaintenance TherapyNo clear guidelines3.5 yrs mean duration – Seven RCTs analysed in KDIGO1.If CR is achieved to continue for atleast 1 year2.If PR alone is achieved continue immunosuppressants3.If frequent relapses continue immunosuppressionNo evidence regarding conversion of PR to CR

Annals of Rheumatic Disease March 2015

AZA or MMF was prescribed per protocol for 5 years Inefficacy or intolerance

The decision to stop or to continue immunosuppressive treatment was left to the patient’s and physician’s decision.

Data from India

• 9 observational studies (1 prospective)• 3 from North, 1 from East, 1 from Central and

4 from South• Response rates varying between 45-82%• 3 in pediatric lupus nephritis – response rates

of 85%

Comparison of three induction regimens

• CR+PR similar between the three groups. (30/40 in the hd cyc group, 12/14 in the elnt cyc group and 15/20 in the mmf group) (p=0.69)

• Complete response rate was higher in the individuals who received Cyclophosphamide (hd cyc + elnt cyc) as compared to mmf (17/34 vs 2/13, p=0.05).

Keerthi T, Varaprasad IR, Uppin M, Rajasekhar L. Outcome of therapy in biopsy proven lupus nephritis with cyclophosphamide or mycophenolate: registry data from a South Indian tertiary care centre. Indian J Rheumatol (Accepted for publication)

Kidney International 2016; 89: 235-242

Screened (n = 173)

Biopsy diagnosis of lupus nephritis class III/IV/V

Reasons for exclusion (n = 73)

Crescentic LN (n = 24)S.creatinine >265.0 µmol/L (n = 16)Previously received CYC or MMF (n = 21)Refused consent (n = 5)Pregnant (n = 1)CNS or pulmonary lupus (n = 6)

50 assigned to receive low fixed dose intravenous CYC

50 assigned to receive MMF as induction agent

Withdrawn (n = 9)

Death (n = 2)Adverse events (n = 3)Lost to follow up (n = 4)

Withdrawn (n = 8)

Death (n = 5)Adverse events (n = 1)Lost to follow up (n = 2)

Completed 24 weeks of follow up (n = 41) Completed 24 weeks of follow up (n = 42)

Randomized (n = 100)

Azathioprine (2 mg/kg) + Prednisolone

Treatment outcomes at 24 weeks

Graph showing comparison of overall and complete response rates (intention to treat analysis) of subjects in two study groups.

CR+PRCR+PR CR

Outcomes: 1 year (APP)

Parameters 6 months 12 months

CYC (n=34)

MMF (n=35)

P value CYC (n=34)

MMF (n=35)

P value

Response 27 (81.8) 28 (80) NS 32 (94.1) 29 (85.3) NS

Remission 17 (51.5) 21 (60) NS 29 (85.3) 28 (82.3) NS

Resistance 6 7 NS 2 6 NS

Death 1 4 NS 1 5 NS

69/83 (83%) subjects have completed one year follow-up.

8 year old boy lupus nephritis Class IV. no hypertension, SPCR 3.5, 24hr UP 0.8 gm, creatinine 0.8 mg/dl, creatinine clearance 85 ml/min. Ht 127 cm, weight 25 kg, BSA 0.93.

3 gm cumulative CYC over 6 months between May 13 to Oct 13.

Maintanence therapy started with azathioprine 50 mg.

Feb 14 SPCR was 0.175.

In Jul 16, he developed proteinuria, SPCR 3.9.

1.What is the risk of sterility with cyclophosphamide in prepubertal children1.Risk is minimal2.Risk increases as puberty approaches3.Irreversible gonadal toxicity is the rule at all ages4.Irreversible gonadal toxicity is seen in females.

• What do the guidelines tell us about the first choice of immunosuppressive in paediatric lupus nephritis?

1. Cyclphosphamide2. Mycophenolate mofetil3. Rituximab4. Tacrolimus

Steroids in lupus nephritis- the time line – Class IV lupus nephritis

1953-1969

17% 5 year

survival

Introduction of corticosteroids

1970-1979

55% 5 year

survival

Moderate vs high dose glucocorticoids

1976: Pulse methyl prednisolone for DPGN

20112014

• Medium dose with methylprednisone pulses + HCQ vs HC(6mth response: 80% vs 47%)• MPA EC with low and high dose GC regimens:20% CR at 24 weeks in both groups

A no steroid regimen

• 58% response rates at 52 weeks• Repeat renal biopsy in 13: 8 had

HR• 1 responded to repeat treatment• 26% relapse at 72 weeks

• Ann Rheum Dis 2013;72:1280–6.

Low dose rhIL-2 in SLE

rhIL-2 1mIU alternate days for 2 weeks 2 weeks break : 3 cycles Nephritis: 18 & 10 patients with proteinuria: 2.71 & 2.18 gm/day

Nature Medicine, 2016

Nature Medicine, 2016

LN New regimen: Mixed martial arts

Individualized therapy in LN